This research will develop rational approaches to the design and synthesis of inhibitors of the aspartyl protease from the feline immunodeficiency virus (FIV) and from the human immunodeficiency virus (HIV-1). It will focus on the following programs: 1. Develop effective and high-affinity small peptide substrates containing a scissle Tyr-Pro bond based on the sequences around the cleavage sites of FIV protease. 2. Investigate the mechanism of FIV protease reaction with synthetic substrates. 3. Design and synthesize Tyr-Pro peptide isostere and transition state analog inhibitors, or mechanism-based inactivators based on its cleavage reaction catalyzed by FIV and HIV protease. 4. Use computer-assisted and mechanism-based rational drug design cycles to improve the potency of inhibitors; incorporate additional peptide or nonpeptide complementarity components to the inhibitors. 5. Develop new chemistry for the synthesis of protease inhibitors in general and aspartyl proteases in particular. Significant contributions in the areas of biomedicine, drug design, and synthetic organic chemistry are expected. These developments will facilitate the discovery and development of new therapeutic agents for AIDS.